It has long been appreciated that visual experience during an early critical period is essential for the normal maturation of visual cortex. Studies on animals reared in different environments have established that during this critical period, visual cortical connections can be modified in an activity dependent manner. Those studies have also shown that visual cortical plasticity depends on neuromodulatory inputs that convey information on the behavioral state of the animals, and on the strength of intracortical inhibition. The goal of this project is to elucidate the cellular mechanisms by which neuromodulators and synaptic inhibition control synaptic modification in visual cortex. This proposal builds upon two recent findings on the regulation of synaptic plasticity in cortex. First, we recently showed that neuromodulators exert a pull-push control of the gain of mechanisms that increase or decrease synaptic strength. Therefore we will investigate whether neuromodulators gate visual cortical plasticity via the pull-push control of synaptic modification, and whether this general mechanism can be recruited to visually induce cortical modifications in the adult brain, after the closure of the critical period. The second avenue opened by our previous research is the realization of a simple mechanism by which neuromodulators can provide a reward signal to guide cortical modifications. Specifically we will test the idea that certain patterns of synaptic activity produce eligibility traces for synaptic modification that need to be subsequently consolidated by the action of neuromodulators. Understanding how synaptic plasticity is regulated can provide essential insight for translational developments. In particular, the possibility of inducing rapid cortical modification with the aid of neuromodulators can be relevant for restoring visual cortical functions in adults. Besides the obvious relevance of neural plasticity to the development of visual capabilities, it is likely that similar processes may form the basis for some forms of learning and memory in the adult brain.